Therapeutic compositions containing macitentan

ABSTRACT

The invention relates to a product containing the compound of formula (I) below or a pharmaceutically acceptable salt of this compound, in combination of at least one compound having prostacyclin receptor (IP) agonist properties, or a pharmaceutically acceptable salt thereof.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation application of U.S. Ser. No.13/058,639, filed on Feb. 11, 2011, now U.S. Pat. No. 8,809,334, whichpatent is a national stage of PCT Application No. PCT/IB2009/053553,filed on Aug. 12, 2009, which claims the benefit of PCT Application No.PCT/IB2008/053252, filed on Aug. 13, 2008, the contents of each of whichare incorporated herein by reference.

The present invention relates to a product containing macitentan, i.e.the compound of formula (I) below

or a pharmaceutically acceptable salt of this compound, in combinationwith at least one compound having prostacyclin receptor (IP) agonistproperties, or a pharmaceutically acceptable salt thereof, as well asthis product for therapeutic use, simultaneously, separately or over aperiod of time, in the treatment of a disease wherein endothelin isinvolved.

PCT publication WO 02/053557 describes endothelin receptor antagonistsincluding the compound of formula (I) and the use of said endothelinreceptor antagonists in the treatment of various diseases whereinendothelin is involved (i.a. heart failure, angina pectoris, pulmonaryand systemic hypertension and erectile dysfunction).

Compounds having prostacyclin receptor (IP) agonist properties have beendescribed notably in the following documents:

-   -   U.S. Pat. No. 4,683,330 describe the compound treprostinil and        salts and analogues thereof;    -   U.S. Pat. No. 4,539,333 describes epoprostenol sodium;    -   U.S. Pat. No. 4,692,464 describe the compound iloprost and salts        and analogues thereof;    -   U.S. Pat. No. 4,474,802 describe the compound beraprost and        salts and analogues thereof;    -   U.S. Pat. No. 7,205,302 describe among others        5,6-diphenylpyrazine derivatives having prostacyclin receptor        (IP) agonist properties, and salts and analogues thereof, an in        particular the compounds known under the code names MRE-269 and        NS-304 (K. Kuwano et al., J. Pharmacol. Exp. Ther. (2007),        322(3), 1181-1188).

Besides, WO 2004/017993 describes the use of the endothelin receptorantagonist bosentan together with the prostacyclin receptor agonistepoprostenol sodium for treating pulmonary arterial hypertension.

The Applicant has now found that the combination of macitentan with acompound having prostacyclin receptor (IP) agonist properties results ina strong synergistic effect in the treatment of diseases whereinendothelin is involved. Additionally, the possible side effects relatedto the compounds having prostacyclin receptor (IP) agonist properties(e.g. flushing or systemic hypotension) are expected to be decreased.

A first subject of this invention relates thus to a product containingmacitentan or a pharmaceutically acceptable salt thereof, and at leastone (and preferably one) compound having prostacyclin receptor (IP)agonist properties, or a pharmaceutically acceptable salt thereof.

A further subject of this invention is a product containing macitentanor a pharmaceutically acceptable salt thereof, in combination with atleast one (and preferably one) compound having prostacyclin receptor(IP) agonist properties, or a pharmaceutically acceptable salt thereof,for therapeutic use, simultaneously, separately or over a period oftime, in the treatment of a disease wherein endothelin is involved.

The following paragraphs provide definitions of the various terms usedin the present patent application and are intended to apply uniformlythroughout the specification and claims, unless an otherwise expresslyset out definition provides a broader or narrower definition.

Macitentan is the recommended INN for the compound of formula (I) andthis name will therefore be used to designate the compound of formula(I) in the present patent application.

“Simultaneously” or “simultaneous”, when referring to a therapeutic use,means in the present application that the therapeutic use concernedconsists in the administration of two or more active ingredients by thesame route and at the same time.

“Separately” or “separate”, when referring to a therapeutic use, meansin the present application that the therapeutic use concerned consistsin the administration of two or more active ingredients at approximatelythe same time by at least two different routes.

By therapeutic administration “over a period of time” is meant in thepresent application the administration of two or more ingredients atdifferent times, and in particular an administration method according towhich the entire administration of one of the active ingredients iscompleted before the administration of the other or others begins. Inthis way it is possible to administer one of the active ingredients forseveral months before administering the other active ingredient oringredients. In this case, no simultaneous administration occurs.Another therapeutic administration over a period of time consists in theadministration over time of the two or more active ingredients of thecombination using different frequencies of administration for each ofthe active ingredients, whereby at certain points in time simultaneousadministrations of all the active ingredients of the combination takeplace whereas at some other points in time only part of the activeingredients of the combination may be administered (for example, in thecase of a combination of macitentan with NS-304, the therapeuticadministration over a period of time could be such that macitentan willbe administered once a day whereas NS-304 will be administered twice aday).

By “disease wherein endothelin is involved” is meant in particularhypertension, pulmonary hypertension (including pulmonary arterialhypertension), diabetic arteriopathy, heart failure, erectiledysfunction, angina pectoris or pulmonary fibrosis.

By “compound having prostacyclin receptor (IP) agonist properties” ismeant a compound that, when submitted to the “Test for the determinationof prostacyclin receptor (IP) agonist EC₅₀” described in the presentpatent application, has an EC₅₀ value equal to or lower than 500 nM.

Specific examples of compounds having prostacyclin receptor (IP) agonistproperties include treprostinil and its pharmaceutically acceptablesalts, epoprostenol and its pharmaceutically acceptable salts, iloprostand its pharmaceutically acceptable salts, beraprost and itspharmaceutically acceptable salts, 2-{4-[(5,6-diphenylpyrazin-2-yl)(isopropyl)amino]butoxy}-N-(methylsulfonyl)acetamide (NS-304) and itspharmaceutically acceptable salts, and{4-[(5,6-diphenylpyrazin-2-yl)(isopropyl)amino]butoxy}acetic acid(MRE-269) and its pharmaceutically acceptable salts.

The term “pharmaceutically acceptable salts” refers to non-toxic,inorganic or organic acid and/or base addition salts. Reference can bemade to “Salt selection for basic drugs”, Int. J. Pharm. (1986), 33,201-217.

Besides, any reference to macitentan or to a compound havingprostacyclin receptor (IP) agonist properties is to be understood asreferring also to the pharmaceutically acceptable salts thereof, asappropriate and expedient.

Preferably, the product according to this invention will be such thatmacitentan and the compound having prostacyclin receptor (IP) agonistproperties are intended for a therapeutic use which takes placesimultaneously or over a period of time.

According to one preferred variant of this invention, macitentan and thecompound having prostacyclin receptor (IP) agonist properties will beintended to be administered simultaneously.

According to another preferred variant of this invention, macitentan andthe compound having prostacyclin receptor (IP) agonist properties willbe intended to be administered over a period of time.

The period of time intended for the therapeutic use of a productaccording to this invention will be at least one week, and preferably atleast one or more months (for example six months). This period of timemay also be the whole life of the patient that receives the product.According to a particular mode of administration according to thisinvention, administration of macitentan will be alternated withadministration of a compound having prostacyclin receptor (IP) agonistproperties, and the interval between such administration will not exceedtwo or three days (and more preferably not exceed one day). According toanother particular mode of administration according to this invention,in the case of a combination of macitentan with NS-304, the therapeuticadministration over a period of time could be such that macitentan willbe administered once a day whereas NS-304 will be administered twice aday.

Preferably, the compound having prostacyclin receptor (IP) agonistproperties will be selected from2-{4-[(5,6-diphenylpyrazin-2-yl)(isopropyl)amino]butoxy}-N-(methylsulfonyl)acetamide(NS-304) and its pharmaceutically acceptable salts, and{4-[(5,6-diphenylpyrazin-2-yl)(isopropyl)amino]butoxy}acetic acid(MRE-269) and its pharmaceutically acceptable salts. According to oneparticularly preferred variant of the invention the compound havingprostacyclin receptor (IP) agonist properties will be2-{4-[(5,6-diphenylpyrazin-2-yl)(isopropyl)amino]butoxy}-N-(methylsulfonyl)acetamide(NS-304) or a pharmaceutically acceptable salt thereof.

The administration route of macitentan and that of the compound havingprostacyclin receptor (IP) agonist properties is preferably the same. Inparticular, the common administration route for macitentan and for thecompound having prostacyclin receptor (IP) agonist properties will bethe oral route.

Though the exact administration doses of a product according to thisinvention will have to be determined by the treating physician, it isexpected that a dose of 0.05 to 2 mg (and preferably 0.1 to 1 mg) ofmacitentan per kg of patient body weight and per day will beappropriate. Similarly, it is expected that a dose of 0.5 to 30 μg (andpreferably 1.5 to 15 μg) of compound having prostacyclin receptor (IP)agonist properties per kg of patient body weight given twice a day willbe appropriate.

Preferably, the disease intended to be treated by a product according tothis invention will be selected from hypertension, pulmonaryhypertension, diabetic arteriopathy, heart failure, erectiledysfunction, angina pectoris and pulmonary fibrosis. More preferably,the disease intended to be treated by a product according to thisinvention will be selected from hypertension and pulmonary hypertension.In particular, the disease intended to be treated by a product accordingto this invention will be pulmonary hypertension (and notably pulmonaryarterial hypertension).

The invention also relates to a pharmaceutical composition containing,as active principles, macitentan or a pharmaceutically acceptable saltof this compound, in combination with at least one (and preferably one)compound having prostacyclin receptor (IP) agonist properties, or apharmaceutically acceptable salt thereof, as well as at least oneexcipient.

The invention further relates to the use of macitentan or apharmaceutically acceptable salt of this compound, in combination withat least one (and preferably one) compound having prostacyclin receptor(IP) agonist properties, or a pharmaceutically acceptable salt thereof,for the manufacture of a medicament intended to treat a disease whereinendothelin is involved.

Besides, preferences indicated for the product according to thisinvention of course apply mutatis mutandis to the pharmaceuticalcompositions and uses of this invention.

Particular embodiments of the invention are described in the followingExamples, which serve to illustrate the invention in more detail withoutlimiting its scope in any way.

EXAMPLES

To illustrate the usefulness of this invention, the association ofmacitentan, administered orally at a dose of 10 mg/kg per day, withNS-304, administered orally at a dose of 1 mg/kg twice a day, can bestudied in two different hypertension models, namely the pulmonaryhypertension monocrotaline rat model and the spontaneously hypertensiverat model. Other associations may of course be tested similarly. Theprotocols that may be used are detailed in the part entitled“Pharmacological properties of the invention compounds” hereafter.

Pharmacological Properties of the Invention Compounds

Experimental Methods:

The experimental methods described hereafter can be used to show thepharmacological properties of the invention compounds.

Monocrotaline Model of Pulmonary Hypertension in Rats

Male Wistar rats are purchased from Harlan (Netherlands) and maintainedunder conditions in accordance with local guidelines (Basel-Landschaftcantonal veterinary office). All rats are housed in climate-controlledconditions with a 12:12 hour light:dark cycle, and had free access tochow and water. A telemetry system is implanted under anaesthesia byinhalation of 2.5% isoflurane (in 70% O₂+30% N₂O). Under asepticconditions, a pressure radio-frequency transmitter is implanted into theperitoneal cavity, and a sensing catheter is inserted in the pulmonaryartery. The transmitter is sutured to the abdominal musculature and theskin is closed. A receiver platform transforms the radio signal intodigitized input, that is sent to a dedicated personal computer (Compaq,Deskpro). Pulmonary arterial blood pressure measurements are calibratedby using an input from an ambient pressure reference. Telemetry unitsare obtained from Data Sciences (St. Paul, Minn., USA). Monocrotaline(MCT; Sigma Chemicals, St Louis, Mo., USA) is administered as a singlesubcutaneous (sc) injection (60 mg/kg) in a volume of 3 ml/kg, andcontrol age-matched rats receive an equal volume of saline.

Variant 1: Chronic Effect Assessment:

The animals are randomly assigned to experimental groups, and treatmentis initiated within 24 h after MCT injection, for a duration of 4 weeks.Macitentan and the compound having prostacyclin receptor (IP) agonistproperties are administered by the oral route. The effects ofmacitentan, the compound having prostacyclin receptor (IP) agonistproperties and their combination on pulmonary arterial blood pressureare measured by collecting data at 5-minute intervals. Hourly means ofpulmonary arterial pressure are calculated for each rat. At the end ofrecording, rats are sacrificed. The heart is removed and weighed, andthe ratio of organ weight to body weight (BW) is calculated. The rightventricle (RV) and the left ventricle plus septum are separated andweighed; the ratio RV/BW is used as an index of right ventricularhypertrophy. The lower the ratio RV/BW, the stronger the effect of theitem(s) tested for reducing right ventricular hypertrophy.

Variant 2: Acute Effect Assessment:

Four weeks after injection of MCT, the rats become pulmonaryhypertensive and the respective effects of a single oral administrationof Macitentan, of the compound having prostacyclin receptor (IP) agonistproperties and of their combination can be evaluated on mean pulmonaryarterial pressure.

Spontaneously Hypertensive Rat Model

The same protocol is used as for the monocrotaline model of pulmonaryhypertension in rats, except that spontaneously hypertensive rats (SHR)replace the monocrotaline-treated rats. The SHR rats are purchased fromHarlan (Netherlands).

Test for the Determination of Prostacyclin Receptor (IP) Agonist EC₅₀:

CHO cells stably expressing the human IP receptor are cultured in Ham'sF-12 medium containing 10% fetal bovine serum in a humidified atmosphereof 95% air and 5% CO₂ at 37° C. Cells are seeded at 1×10⁵ cells/well in24-well plates and cultured for 48 h. Following a wash and incubationwith assay buffer for 1 h at 37° C., the cells are exposed to variousconcentrations of test compound in the presence of IBMX (500 μM). Afterremoval of supernatant, the reaction is stopped by addition of 0.2 Mperchloric acid. Adherent cells are frozen for 2 h at −80° C. and thawedto extract intracellular cAMP. Supernatants are collected in tubes,neutralized by 2M KHCO₃ solution, and then centrifuged at 14,000 g for10 min at 4° C. to obtain samples for measurement of cAMP levels by EIAsystem. Protein content of cell debris adhered to culture plates ismeasured following solubilization in 1N NaOH solution. Levels of cAMPare expressed as pmol cAMP/mg protein. The EC₅₀ value is determined fromnon-linear regression analyses of concentration-response curves, and isdefined as the negative logarithm of the concentration of test compoundthat elicits a response that is half of the maximal effect observed.

Experimental Results:

Example 1 Acute Effect of Macitentan, NS-304 and Their Combination onMean Pulmonary Arterial Pressure in Monocrotaline Treated Rats

Experiments were performed in pulmonary hypertensive male Wistar ratstreated with monocrotaline according to the monocrotaline model asdescribed in the section “Monocrotaline model of pulmonary hypertensionin rats” of the part entitled “Experimental methods”.

25 to 30 days after the monocrotaline treatment, four groups of 6 ratswere formed and studied:

-   -   the first group was treated neither with macitentan nor with        NS-304 (control group);    -   the second group was treated with macitentan only (10 mg/kg per        os);    -   the third group was treated neither with NS-304 only (30 mg/kg        per os);    -   the fourth group was treated with a combination of macitentan        (10 mg/kg per os) and NS-304 (30 mg/kg per os).

Mean pulmonary arterial pressure was measured over time. Therelationship between mean pulmonary arterial pressure and time wasplotted as a graph. Area Under Curve (AUC) was calculated for each groupof rats after the oral administration of the different treatment(s) (apositive area being found if the mean pulmonary arterial blood pressureincreases and a negative area being found if the mean pulmonary arterialblood pressure decreases). The results thus obtained are summarized inTable 1 hereafter.

TABLE 1 Rat group [treatment] AUC Group 1 [control: no treatment]  106 ±134 Group 2 [treatment with macitentan (10 mg/kg per os)] −381 ± 147Group 3 [treatment with NS-304 (30 mg/kg per os)]  −99 ± 128 Group 4[treatment with macitentan (10 mg/kg per os) and −758 ± 164 NS-304 (30mg/kg per os)]

These data obtained in the monocrotaline model of pulmonary arterialhypertension confirm the synergistic effect of a combination ofmacitentan and NS-304 in the treatment of rats having previouslyundergone monocrotaline administration.

The invention claimed is:
 1. A method for the treatment of a diseaseselected from hypertension, pulmonary hypertension, diabeticarteriopathy, heart failure, erectile dysfunction, angina pectoris andpulmonary fibrosis, comprising administering an effective amount of thecompound of formula (I)

in free or pharmaceutically acceptable salt form, in combination with aneffective amount of at least one compound having prostacyclin receptor(IP) agonist properties selected from2-{4-[(5,6-diphenylpyrazin-2-yl)(isopropyl)amino]butoxy}-N-(methylsulfonyl)acetamideand {4-[(5,6-diphenylpyrazin-2-yl)(isopropyl)amino]butoxy}acetic acid,in free or pharmaceutically acceptable salt form.
 2. The methodaccording to claim 1, wherein the compound having prostacyclin receptor(IP) agonist properties is{4-[(5,6-diphenylpyrazin-2-yl)(isopropyl)amino]butoxy}acetic acid, infree or pharmaceutically acceptable salt form.
 3. The method accordingto claim 1, wherein the compound having prostacyclin receptor (IP)agonist properties is2-{4-[(5,6-diphenylpyrazin-2-yl)(isopropyl)amino]butoxy}-N-(methylsulfonyl)acetamide,in free or pharmaceutically acceptable salt form.
 4. The methodaccording to claim 1, wherein the compound of formula (I) and thecompound having prostacyclin receptor (IP) agonist properties areadministered simultaneously, separately or over a period of time.
 5. Themethod according to claim 1, wherein the disease is pulmonaryhypertension.
 6. The method according to claim 1, wherein the disease ispulmonary arterial hypertension.
 7. The method according to claim 6,wherein the compound of formula (I) is in free form.
 8. The methodaccording to claim 7, wherein the compound of formula (I) and thecompound having prostacyclin receptor (IP) agonist properties areadministered simultaneously.
 9. The method according to claim 7, whereinthe compound of formula (I) and the compound having prostacyclinreceptor (IP) agonist properties are administered separately.
 10. Themethod according to claim 7, wherein the compound of formula (I) and thecompound having prostacyclin receptor (IP) agonist properties areadministered over a period of time.
 11. The method according to claim 6,wherein the compound of formula (I) and the prostacyclin receptor (IP)agonist are administered orally.
 12. The method according to claim 1,wherein the compound of formula (I) and the prostacyclin receptor (IP)agonist are administered orally.
 13. A method for the treatment ofpulmonary arterial hypertension comprising administering an effectiveamount of the compound of formula (I)

in free or pharmaceutically acceptable salt form, in combination with aneffective amount of2-{4-[(5,6-diphenylpyrazin-2-yl)(isopropyl)amino]butoxy}-N-(methylsulfonyl)acetamide,in free or pharmaceutically acceptable salt form.
 14. The methodaccording to claim 13, wherein the compound of formula (I) and2-{4-[(5,6-diphenylpyrazin-2-yl)(isopropyl)amino]butoxy}-N-(methylsulfonyl)acetamideare administered simultaneously.
 15. The method according to claim 13,wherein the compound of formula (I) and2-{4-[(5,6-diphenylpyrazin-2-yl)(isopropyl)amino]butoxy}-N-(methylsulfonyl)acetamideare administered separately.
 16. The method according to claim 13,wherein the compound of formula (I) and2-{4-[(5,6-diphenylpyrazin-2-yl)(isopropyl)amino]butoxy}-N-(methylsulfonyl)acetamideare administered over a period of time.
 17. The method according toclaim 13, wherein the compound of formula (I) is administered once aday.
 18. The method according to claim 13, wherein2-{4-[(5,6-diphenylpyrazin-2-yl)(isopropyl)amino]butoxy}-N-(methylsulfonyl)acetamideis administered twice a day.
 19. The method according to claim 13wherein the compound of formula (I) and the prostacyclin receptor (IP)agonist are administered orally.